The present invention provides oral compositions comprising a zinc compound containing free available zinc and at least one stabilized or stable Eh raising compound distributed in an oral vehicle. The present invention is further directed to a method of inhibiting the formation of anionic sulfur species in the oral cavity and preventing a lowering of the Eh of the oral cavity. A method of simultaneously reducing oral malodor, gingivitis and periodontitis by preventing or reducing oral putrefaction is also provided by this invention.
The hard and soft tissues of the mouth are covered with microbial populations that contain bacteria with different metabolic capabilities. The Gram-positive bacteria within these microbial populations readily catabolize carbohydrates to produce acids which attack the hard tissues of the oral cavity, resulting in the formation of dental caries lesions (cavities). In contrast, the Gram-negative bacteria, especially the anaerobes readily metabolize various amino acids contained in salivary (and to lesser extent other) peptides and proteins in the oral cavity to form end-products which favor the formation of oral malodor and periodontitis. This process of peptide, protein and amino acid degradation by the mouth bacteria is referred to as oral bacterial putrefaction. The mixture of malodorous compounds produced by the Gram-negative anaerobic bacteria during putrefactive degradation of proteins, peptides and amino acids include hydrogen sulfide, methyl mercaptan, and dimethyl sulfide (formed from the sulfur containing amino acids cysteine, cystine and methionine); indole and skatole (formed during the metabolism of tryptophan); cadaverine and putrescine (produced from lysine and ornithine); and butyrate and valerate (produced from the metabolism of other amino acids). The production of these malodorous compounds in the oral cavity results in a condition commonly referred to as oral malodor.
Hydrogen sulfide, methyl mercaptan, butyrate and propionate are putrefaction end-products that also have cell and tissue altering non-inflammatory roles in the periodontitis process. Hydrogen sulfide and methylmercaptan are compounds particularly effective in facilitating the oral epithelium penetrability of toxins and other large molecular weight compounds produced by Gram-negative bacteria, and leading to the inflammation and tissue degradation characteristics of gingivitis and periodontitis. Gingivitis is a condition in which the gingiva is red, swollen and bleeding. If left untreated, gingivitis may develop into periodontitis, a condition characterized by destruction of the periodontium, including epithelial attachment loss, periodontal membrane and ligament destruction, and loss of gingiva and alveolar bone. Severe periodontitis resulting in deep periodontal pockets may ultimately result in tooth loss.
Previous studies have largely focused on the use of germicidal agents to treat gingivitis-periodontitis and oral malodor. Until the findings by the present invention, previous studies have not recognized that gingivitis-periodontitis and oral malodor arise from a common process, oral bacterial putrefaction; also that this putrefaction can be inhibited by simultaneously lowering the ability of the oral bacteria to reduce the oxidation-reduction potential (Eh) of the oral cavity and at the same time, raising the existing Eh to where the oral environmental Eh is not conducive to oral putrefaction and oral disease production.
The metabolism and growth of anaerobic bacteria in the oral cavity is favored when the Eh. is lowered. The present invention has discovered that the oxidation-reduction potential (Eh) is a key regulating factor in oral bacterial putrefaction. The lowering of the Eh of the oral cavity has been found to occur in two steps, a depletion of oxygen followed by the generation of electron rich compounds. The present invention has discovered from studies on the isolation and catabolism by the oral bacteria of nitrogenous substrates in human saliva that the primary compounds responsible for lowering the Eh of the oral cavity are non-volatile sulfur containing anions derived largely from cysteine and cystine (Table 1). These include the anionic sulfur species, sulfide (S=), hydrogen sulfide (HSxe2x88x92) and methyl mercaptan (CH3Sxe2x88x92). Such anions favor an ecological environment of reduction (lower Eh) that enables the Gram-negative anaerobic bacteria in the mouth to grow, engage in oral putrefaction and produce electron-rich compounds leading to and maintaining a prolonged lowering of the Eh of the oral cavity and the undesirable conditions of oral malodor, gingivitis and periodontitis. A lower Eh favors the oral bacterial putrefaction process whereas a higher Eh is inhibitory.
The present invention provides compounds that simultaneously (i) inhibit the formation of these electron-rich compounds and thereby prevent the Eh from falling to harmful levels and (ii) react with any electron-rich compounds formed and by thus neutralizing them, raise the Eh to safer levels. It has been surprisingly discovered in accordance with the present invention that an oral composition containing a zinc compound capable of providing free available zinc and a stabilized or stable Eh raising compound can effectively prevent the lowering of the Eh. This is crucial to preventing oral bacterial putrefaction, the metabolic process that is the basis and that results in the development of both oral malodor and gingivitis-periodontitis.
Zinc compounds, hydrogen peroxide, and chlorine dioxide have each been used as therapeutic agents in oral compositions to destroy harmful bacteria involved in oral malodor and gingivitis-periodontitis formation. Previous studies where zinc has been identified as having anti-microbial and anti-plaque effects have made no distinction between zinc compounds where the zinc is freely available and where it is not. (See for example, U.S. Pat. No. 4,289,755 to Dhabhar). The zinc species is an important element of this invention, since free available zinc (zinc ion) within the oral cavity is required to inhibit the Eh lowering capability of a pathogenic, putrefactive microbiota. Zinc compounds used in the compositions previously described include compounds where zinc is not freely available. Zinc that is bound or complexed to various ligands and zinc species that have a low solubility and form precipitates are prevented from reacting with the Eh lowering enzymes and products produced by the putrefactive microbiota and hence are poorly suited for the purposes of this invention.
The solubility for zinc compounds vary as shown in the table below.
Data are from the Handbook of Chemistry and Physics, Chemical Rubber Company, 67th Edition CRC Press, Boca Raton, Fla., 1986-87.
It is evident from this table that the amount of zinc that will be soluble and available in the oral cavity for controlling pathogenic microbiota will vary considerably. Those zinc compounds that provide low levels of zinc ion in solution, such as zinc oxide, are unsuitable for the present invention. This distinction between the various zinc compounds was not recognized prior to this invention. In essence, in order to inhibit the Eh from falling to harmful levels, it is essential that the zinc ions are freely available.
Previous studies have also identified hydrogen peroxide and chlorine dioxide as germicidal agents. The chlorine dioxide is usually derived from the chlorite ion. Hydrogen peroxide owes its germicidal activity to oxygen release and formation of free radicals which provides chemical and mechanical mechanisms for killing oral anaerobic bacteria and cleaning wounds and removing tissue and other debris from inaccessible areas (such as between the teeth). The release of oxygen from hydrogen peroxide is particularly pronounced in the presence of catalase, organic matter, metals and metal compositions. In this invention, this is inhibited from happening by use of chloride ion, so that the peroxide will serve as an Eh raising compound rather than as a germicidal agent. U.S. Pat. Nos. 5,104,644, 5,174,990 and 5,310,546 to Douglas describe the use of hydrogen peroxide as such a germicidal agent. Specifically in the oral composition described by Douglas, hydrogen peroxide releases molecular oxygen in the presence of tissue catalase and peroxidase to act against the oral anaerobic bacteria. Previous studies do not stabilize the hydrogen peroxide so that it does not break down.
The oral composition described herein acts as an Eh raising compound rather than one that results in formation of breakdown products. In this invention, degrading these species to produce a germicidal effect, is avoided. The hydrogen peroxide in the composition described herein is stabilized using chloride ion, an acidic pH, and avoiding mixing it with zinc ion until just before use.
Chlorine dioxide is an oxyhalogen compound widely used in industry for disinfection and control of bacterial biofouling. It is also used to control taste, odor, oxidation of metal ions and color removal in other applications. Several studies have described using chlorine dioxide as an antimicrobial agent in mouth rinse applications. For example, U.S. Pat. No. 4,696,811 to Ratcliff describes a method and composition to destroy malodorous compounds; Patent No. UK 2290233A to Drayson and Butcher describes compositions for tooth whitening. Others include inventions where the oxidizing and germicidal capabilities of chlorine dioxide are activated by forming chlorine dioxide just prior to use. The main reason chlorine dioxide is generated in this way is because chlorine dioxide is an unstable gas at room temperature (boiling point of 11xc2x0 C.) and is sensitive to decomposition by visible and ultraviolet light. In previous studies, the chlorine dioxide is commonly generated from the chlorite ion by acidification. It is usually provided as sodium chlorite buffered to a pH around 7 to 8 and above, and as such, referred to as stabilized chlorine dioxide (U.S. Pat. Nos. 4,689,215 and 4,837,009 to Ratcliff, Patent No. UK 2290233A to Drayson and Butcher and Patent No. WO 95/27472 to Richter). Chlorine dioxide like hydrogen peroxide above, is typically generated for the purpose of killing mouth bacteria. Where acidification of chlorite is carried out, the levels of chlorine dioxide produced are usually adequate for its germicidal purpose. But in those compositions where chlorine dioxide is stabilized as sodium chlorite at neutral or alkaline pH, formation of chlorine dioxide from chlorite ion is a relatively slow process. Accordingly, very little chlorine dioxide is available within the oral cavity as an antibacterial agent in these compositions. In contrast, in the compositions herein, chlorite ions are not used as germicidal agents. Instead they are used as effective and stable Eh raising compounds, if their degradation to chlorine dioxide is avoided.
In previous inventions, chlorite ion use involves provision (rather than removal) of electrons to enable chlorite ion disproportionation and formation of the bacteriocidal compound, chlorine dioxide, a process stimulated by acid addition. The oxidation-reduction change involves change in oxidation state from +3 to +4. On the other hand, when chlorite acts as an Eh raising compound as in the invention herein, its oxidation state decreases from +3 to xe2x88x921. Reduction of chlorite ion is to chloride ion after going through a series of reactions involving various intermediates. What is evident from this analysis is that the chlorite ion is capable of acting as either an oxidizing or as a reducing agent depending upon the reaction conditions. Few compounds show such multi-step, and hence atypical redox buffer effects. Nonetheless, this enables them to counter or resist along with zinc ion the kinds of changes in the Eh level that enable oral putrefaction to flourish and be suitable for this invention.
Using sodium chlorite as an Eh raising compound rather than as a source of chlorine dioxide is very important, because chlorine dioxide at elevated levels combines with certain amino acids to produce compounds that are potentially mutagenic. Therefore, inhibition or prevention of significant chlorine dioxide formation from sodium chlorite is desirable and preferred and contra-indicated is the utilizing of sodium chlorite to generate large amounts of chlorine dioxide therefrom in order to kill enough bacteria to have significant oral effects.
A neutral pH and above is essential for chlorite ion stability and to avoid chlorine dioxide formation. Also, chloride ion is useful for additional stabilization of the sodium chlorite where there is any decrease in the pH. This is because chloride ion is produced when chlorite becomes chlorous acid and disproportionation of chlorous acid occurs
xe2x80x835HClO2xe2x86x924ClO2+Clxe2x88x92+H++2H2O
This reaction is inhibited by mass action when chloride ion is provided.
Hydrogen peroxide like sodium chlorite behaves as an Eh raising compound in that it can also readily react as either an oxidizing or a reducing agent. Analogous to the chlorine dioxide/chlorite/chloride system is the molecular oxygen/hydrogen peroxide/water system where chlorite ion and hydrogen peroxide. are similarly positioned as oxidation-reduction intermediates. In previous studies, the peroxide is used to generate oxygen and/or oxygen reactive species to kill the oral bacteria involved in oral disease. As found for chlorite ion, peroxide in this invention functions as an Eh raising compound by removing the excess electrons of putrefaction and producing hydroxyl ions rather than giving up electrons and undergoing disproportionation as in previous patents.
The disproportionation reaction of hydrogen peroxide
2H2O2xe2x86x922H2O+O2
is very slow under ordinary conditions but rapid in the presence of the enzymes, catalase and peroxidase, found in certain of the bacteria in the oral cavity. Once again, hydrogen peroxide is a species like chlorite ion that is thermodynamically unstable with respect to disproportionation and can function as an intermediate in oxidation-reduction reactions. Further and once again, the chloride ion inhibits the disproportionation of hydrogen peroxide but does so through inhibition of catalase.
The oxygen-oxygen single bond in hydrogen peroxide is one of the weakest covalent bonds known. It is easily broken indicating that it readily accepts electrons and as a result is able to produce hydroxyl ions. Alternatively, hydrogen peroxide is converted into the stable oxygen molecule. Previous studies have shown, using 18O labeled hydrogen peroxide, that the oxygen produced is derived entirely from the peroxide species and not from water. This suggests that the breakdown of peroxide does not involve the breaking of the Oxe2x80x94O bond but provides electrons to an appropriate oxidizing agent. H2O2 when used as an Eh raising compound is not used as a source for molecular oxygen.
Recent studies by Douglas (U.S. Pat. Nos. 5,104,644, 5,174,990, and 5,310,546) have described oral compositions combining zinc chloride and hydrogen peroxide to treat gingivitis-periodontitis. U.S. Pat. No. 5,174,990 describes a mouth rinse containing zinc chloride and hydrogen peroxide. In these Douglas patents, it is necessary to counter the instability prior to use of the formulations described, which is caused largely because of the presence of zinc metal. To aid in stabilization of zinc, ligands that bind well to zinc such as citrate and laurylsulfate are added. However, these additions reduce the availability of free zinc, especially when these ligands are present at high ligand to zinc ratios. The mouth rinses in U.S. Pat. Nos. 5,174,990 and 5,310,546 have zinc chloride concentration ranging from 0.005% to 0.1% and a hydrogen peroxide concentration ranging from 0.25% to 0.65%. In the absence of ligands that bind zinc, zinc ion at these zinc chloride levels range in concentration between 0.002% and 0.047%. Moreover, recent studies have shown that hydrogen peroxide at the concentrations described therein are degraded by oral bacterial catalase and are not effective in vivo. Ryan and Kleinberg (1995) Archs. oral Biol., 40, 753-763. Accordingly, to compensate for the rapid breakdown of hydrogen peroxide by catalase, use of higher concentrations of hydrogen peroxide (1% or above) is necessary. At hydrogen peroxide concentrations above 3.0 to 3.5%, studies have shown that hydrogen peroxide can be harmful to the soft tissues of the oral cavity. Thus, for an oral composition containing hydrogen peroxide to be effective as a therapeutic and at the same time not harm the soft or hard tissues of the oral cavity or be harmful if swallowed, its concentration needs to be between about 1% and 3%.
In contrast, the oral compositions discovered in this invention contain sufficient chloride ions to inhibit catalase hydrolysis of the peroxide, thereby enabling peroxide to remain intact even at lower peroxide levels than 1% and for the peroxide to serve as an Eh raising compound where formation of toxic products from peroxide are avoided.
Many reactions involving hydrogen peroxide in solution result in the production of free radical species, such as HO2 and OH. These are effective agents for killing bacteria and such formation is a basis for the use of hydrogen peroxide as a disinfectant. Transition metal-ion catalyzed decomposition of hydrogen peroxide can readily give rise to the formation of free radicals. The destabilizing effects of zinc are avoided in this invention by using a two compartment approach where combination with zinc compound is provided just prior to use to ensure maximum availability of free zinc. The compositions described herein result in a synergism between the zinc ions, the peroxide used as an Eh raising compound and the chloride ions. This two compartment system is a more desirable and effective approach than oral compositions previously described.
Methylene blue has been used as an Eh raising compound. It readily accepts electrons and in this way helps prevent the electron accumulation that produces the low Eh that favors oral putrefaction. In U.S. Pat. No. 5,087,451 to Wilson and Harvey, methylene blue is used to inhibit periodontitis. The beneficial effect of methylene blue alone is significantly less than achieved when used in conjunction with zinc ion as with the compositions of this invention.
The present invention is directed to oral compositions containing a zinc compound where zinc ion is freely available and at least one stabilized or stable Eh raising compound distributed in an oral vehicle. In one embodiment, the oral compositions contain a zinc compound containing freely available zinc ions, hydrogen peroxide and a chloride ion containing compound. In another embodiment, the oral composition contains a zinc ion compound and an oxyhalogen compound. A further embodiment of this invention includes an oral composition containing a zinc ion compound and methylene blue.
The present invention is further directed to a method of inhibiting the formation of anionic sulfur species and thereby preventing a lowering of the Eh of the oral cavity. Specifically, the method comprises delivering into the oral cavity a therapeutically effective amount of an oral composition containing a free available zinc compound and at least one stabilized or stable Eh raising compound distributed in an oral vehicle.
A further embodiment of the present invention is a method of reducing both oral malodor and gingivitis-periodontitis comprising delivering into the oral cavity a therapeutically effective amount of an oral composition containing a zinc ion compound and at least one stabilized or stable Eh raising compound.